Identification of prognostic markers in diffuse midline gliomas H3K27M‐mutant

Abstract

Pediatric diffuse midline gliomas are devastating diseases. Among them, diffuse midline gliomas H3K27M-mutant are associated with worse prognosis. However, recent studies have highlighted significant differences in clinical behavior and biological alterations within this specific subgroup. In this context, simple markers are needed to refine the prognosis of diffuse midline gliomas H3K27M-mutant and guide the clinical management of patients. The aims of this study were (i) to describe the molecular, immunohistochemical and, especially, chromosomal features of a cohort of diffuse midline gliomas and (ii) to focus on H3K27M-mutant tumors to identify new prognostic markers. Patients were retrospectively selected from 2001 to 2017. Tumor samples were analyzed by immunohistochemistry (including H3K27me3, EGFR, c-MET and p53), next-generation sequencing and comparative genomic hybridization array. Forty-nine patients were included in the study. The median age at diagnosis was 9 years, and the median overall survival (OS) was 9.4 months. H3F3A or HIST1H3B mutations were identified in 80% of the samples. Within the H3K27M-mutant tumors, PDGFRA amplification, loss of 17p and a complex chromosomal profile were significantly associated with worse survival. Three prognostic markers were identified in diffuse midline gliomas H3K27M-mutant: PDGFRA amplification, loss of 17p and a complex chromosomal profile. These markers are easy to detect in daily practice and should be considered to refine the prognosis of this entity.Dufour et al Prognostic markers in diffuse gliomas H3K27M-mutant Brain Pathology 30 (2020) [179][180][181][182][183][184][185][186][187][188][189][190]

Mutations within FGFR1 are associated with superior outcome in a series of 83 diffuse midline gliomas with H3F3A K27M mutations

“…Diffuse midline glioma (DMG), H3 K27M mutant (WHO grade IV) is listed as a separate CNS tumor entity since 2016 [5], after large sequencing efforts had discovered H3 K27M mutations frequently appearing in gliomas located in midline structures [11]. Over time, we and others have observed single cases of DMG with concomitant mutations within FGFR1 or BRAF [1,2,4,6,7,9,10,[12][13][14]. FGFR1 and BRAF mutations are typical hallmarks of low grade glioma, such as pilocytic astrocytoma, ganglioglioma, or dysembryoplastic neuroepithelial tumor [3,8].…”

Paediatric Gliomas: BRAF and Histone H3 as Biomarkers, Therapy and Perspective of Liquid Biopsies

“…Wu et al [16] reported that 78% of H3K27M mutations are detected in diffuse intrinsic pontine glioma, approximately 60% and 18% of which involve the H3F3A gene and HIST1H3B gene, respectively. Most recently, Dufour et al [61] studied 49 patients with paediatric diffuse midline glioma and discovered that 80% of the tumour carried H3K27M mutations, of which 63.6% and 15.9% of the H3F3A and HIST1H3B genes, respectively, were mutated. The studies demonstrated that H3F3A and HIST1H3B mutations are common in the pHGGs derived from midline locations of the brain.…”

“…Paediatric groups that suffer from diffuse intrinsic pontine glioma containing H3K27M mutations have a worse prognosis with a median survival of 0.73 years, as compared to those harbouring wild-type tumours: 4.59 years [67]. Similarly, children with diffuse midline glioma also show poor prognosis, with a median overall survival (OS) of 0.78 years [61]. Generally, many studies concluded that pHGGs with H3K27M mutations are always associated with a worse prognosis.…”

“…However, Castel et al [67] demonstrated that molecular alterations and clinical behaviour within H3.1K27M and H3.3K27M could affect the patients' prognoses. Most recently, a retrospective study introduced three prognostic markers to refine diffuse midline glioma prognosis: the loss of 17p, PDGFRA amplification and a complex chromosomal profile [61]. These three markers are associated with worse survival in diffuse midline glioma patients.…”

Genomic Profiling Identified Novel Prognostic Biomarkers in Chinese Midline Glioma Patients

“…In addition to H3 K27M, ATRX, TP53, NF1, FGFR1, PDGFRA, PTPN11, and BRAF alterations have been found in various pediatric and adult midline glioma subtypes, while 1p/19q co-deletion were seldom reported (8,12,14,18,19). Many of these frequently observed genes are key members of PI3K/mTOR and RAS-MAPK pathways that could potentially provide novel therapeutic options for these otherwise devastating diseases (20)(21)(22)(23)(24). Nevertheless, the prognostic significance of genetic aberrations and oncogenic pathways was only weakly addressed for midline glioma with or without H3 K27M mutation (20) and comprehensive molecular characterization is still lacking.…”